The present invention relates to processes for making fulvestrant and intermediates useful in the preparation. Fulvestrant is the generic name for (7α,17β)-7-{9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl}estra-1,3,5(10)-triene-3,17-diol having the following formula (I)
and was first disclosed in EP 0138504.
Fulvestrant is used to treat locally advanced or metastatic breast cancer in women who have been through menopause. In US, it is sold under brand name FESLODEX.
There are several references reporting the preparation of Fulvestrant, for example WO 2002/32922, WO 2005/077963, Synthesis December 1995, pages 1493-1495, WO 2005/077968, WO 2006/015081, WO 2009/013310 and WO 2010/043404.
The above given references provide a general process for the preparation of Fulvestrant which is summarized in FIG. 1,
wherein, R is a protecting group.
The process depicted in FIG. 1 can be described as follows:                The hydroxyl groups at C-3 and C-17 of Estradiol (compound 1) are protected to give compound 2.        Compound 2 is deprotonated and the resulting anion is converted to compound 3 (mixture of 6α and 6β epimers in 4:1 ratio).        Compound 3 is oxidized to obtain compound 4.        Compound 4 is alkylated to compound 5 and deprotected to obtain a compound 6.        Compound 6 is further oxidized to give Fulvestrant.        
The oxidation of 6-OH group of compound 3 is very important to get higher industrial yield. All prior disclosed processes mentioned above provide very low yield of compound 4 and hence overall yield of Fulvestrant is reduced. For example, use of aqueous Sodium hypochlorite as oxidizing agent in the process described in Synthesis, December 1995, Pages 1493-1495 gives a yield of 73%. Similarly Pyridinium chlorochromate (PCC) used in WO 2005/077968 gives only 51% yield.
As per WO 2005/077968, the reaction yield obtained for the conversion of compound 2 to compound 4 is 43% only; whereas in Synthesis December 1995, pages 1493-1495, the yield is only 64%.
Chromium (VI) reagents and other reagents derived from dimethyl sulfoxide are commonly used reagents for the oxidation of alcohols to ketones. These reactions require longer reaction times and it is often necessary to use several fold excess of these reagents to obtain a high yield of oxidized product. Workup procedures for chromium (VI) oxidations are more complicated. All chromium (VI) reagents produce solid chromium-containing byproducts, which cannot be removed by extraction, necessitating time-consuming filtration or chromatographic procedure. All chromium containing reagents are, of course toxic and carcinogenic which are not suitable for pharmaceutical preparations.
Thus, there is a need for developing a novel and environmental friendly and better yielding oxidation process at position 6 of the steroid molecule.
Further compound 4 is converted to compound 5 by alkylation in a single step. This direct alkylation results in low yield and produces unwanted 7β epimer. Thus there is a need to provide a better yielding process which reduces the unwanted 7β epimer.